Diabetes mellitus is among the most common of all metabolic disorders, affecting up to 11% of the population by age 70. Type I diabetes (insulin dependent diabetes mellitus or IDDM) represents about 5 to 10% of this group and is the result of a progressive autoimmune destruction of the pancreatic .beta.-cells with subsequent insulin deficiency.
There are two classes of type II diabetes (non-insulin dependent diabetes mellitus or NIDDM). One typically presents in older people; thus it is sometimes called mature onset diabetes. Another form, though similar to mature onset, presents in a subject at a very early age. Type II diabetes represents 90-95% of the affected population, more than 100 million people worldwide (King, H. and Zimmer, P. (1988) Wld Hlth. Statist. Quart. 41:190-196; Harris, M. I., et al. (1992) Diabetes Care 15:815-819), and is associated with peripheral insulin resistance, elevated hepatic glucose production, and inappropriate insulin secretion (DeFronzo, R. A. (1988) Diabetes 37:667-687). Family studies point to a major genetic component (Newman, B. et al. (1987) Diabetologia 30:763-768; Kobberling, J. (1971) Diabetologia 7:46-49; Cook, J. T. E. (1994) Diabetologia 37:1231-1240). However, few susceptibility genes have been identified.
Certain loci have been linked to rare early-onset forms of Type II diabetes that is associated with chronic hyperglycemia and monogenic inheritance (i.e. maturity onset diabetes of the young (MODY) loci) (Bell, G. I. et al. (1991) Proc. Natl. Acad. Sci. USA 88:1484-1488; Froguel, P. et al. (1992) Nature 356:162-164; Hattersley, A. T. et al. (1992) Lancet 339:1307-1310; Vaxillaire, M. et al. (1995) Nature Genet. 9:418-423. The defects in the glucokinase (GCK) gene on human chromosome 7 have been found to be responsible for the relatively rare MODY (MODY2) (Froguel, P. et al. (1992) Nature, 356:162-164).
Linkage studies have shown that a different gene associated with MODY is tightly linked to the adenosine deaminase gene (ADA) on human chromosome 20q. This as yet unidentified gene is referred to as MODY1. (Bell, G. I. et al., (1991) Proc. Natl. Acad. Sci. USA, 88:1484-1488; Cox, N. J. et al., (1992) Diabetes, 41:401-407; Bowden, D. W. et al., (1992), Diabetes, 41:88-92). The MODY1 locus has since been refined to a 13 centimorgan interval (about 7 Mb) on chromosome 20 in bands q11.2-q13.1 (Rothschild, C. B. et al., (1992) Genomics 13:560-564). A yeast artificial chromosome-based map of the region has been made (Stoffel, M. et al., (1996) Proc. Natl. Acad. Sci. USA 93:3937-3941). A number of studies have failed to find linkage NIDDM with the MODY1 region (Baroni, M. G. et al., (1992) Diabetes 41:1640-1643; Dow, E. et al., (1994) Diabet. Med. 11: 856-861; Chuang, L. M. et al., (1995) Diabetolgia 38:1490-1491).
Linkage studies have also shown that yet a further gene responsible for MODY is contained within a 7 centimorgan interval bracketed by D12586 and D125342 on human chromosome 12q. This as yet unidentified gene is referred to as MODY3. (Vaxillaire, M. et al., (1995) Nature Genetics, 9:418-423). One study reports that this locus is not implicated in certain late-onset NIDDM (Lesage, S. et al., (1995) Diabetes, 44:1243-1247).
Another locus has been identified for a rare early-onset form of type II diabetes with mitochondrial inheritance (Van den Ouwenland, J. M. W. et al., (1992) Nature Genet. 1:368-371). In addition, Harris et al. (Harris, C. L. et al. (1996) Nature Genet. 13:161-166) have identified a type II diabetes linked locus on chromosome 2, referred to as NIDDM1, that appears to play a role in Mexican American diabetes. Further, Mahtani et al., (Mahtani, M. M. et al. (1996) Nature Genetics 14:90-94) report evidence of the existence of a gene on human chromosome 12, referred to as NIDDM2, that causes NIDDM associated with low insulin secretion.
Effective therapies for type II diabetes are needed.